Journal article
TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia
Acta neuropathologica, v 127(3), pp 397-406
03 Jan 2014
PMID: 24385136
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Variants in transmembrane protein 106 B (
TMEM106B
) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (
GRN
) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (
C9ORF72
) expansions. We assessed the genotype of 325
C9ORF72
expansion carriers (cohort 1), 586 FTD patients lacking
C9ORF72
expansions (with or without motor neuron disease [MND]; cohort 2), and a total of 1,302 controls for
TMEM106B
variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with
C9ORF72
expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls (11.9% versus 19.1%, odds ratio (OR): 0.57, p=0.014; same direction as carriers of
GRN
mutations). The strongest evidence was provided by FTD patients (OR: 0.33, p=0.009) followed by FTD/MND patients (OR: 0.38, p=0.017), whereas no significant difference was observed in MND patients (OR: 0.85, p=0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR: 0.77, p=0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR: 0.26, p<0.001).
Our study identifies
TMEM106B
as the first genetic factor modifying disease presentation in
C9ORF72
expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of
TMEM106B
are not confined to carriers of
GRN
mutations, and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.
Metrics
Details
- Title
- TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia
- Creators
- Marka van Blitterswijk - Mayo ClinicBianca Mullen - Mayo ClinicAlexandra M. Nicholson - Mayo ClinicKevin F. Bieniek - Mayo ClinicMichael G. Heckman - Mayo ClinicMatthew C. Baker - Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA Section of Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA Division of Neurology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada Department of Neurology, University of California, 500 Parnassus Ave, San Francisco, CA 94143, USA The University of Western Ontario, 1151 Richmond St, London, ON N6A 3K7, Canada Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, 320 East Superior Street Chicago, IL 60611, USA University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA Molecular Brain Research Group, Robarts Research Institute, 100 Perth Drive London, ON N6A 5K8, Canada Banner Sun Health Research Institute, 10515 W Santa Fe Dr, Sun City, AZ 85351, USA Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA Department of Neurology, Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129, USA Department of Neurology, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ 85054, USA Department of Neurology, Mayo Clinic, 1216 2nd St SW, Rochester, MN 55902, USA Department of Pathology and Laboratory Medicine, University of British Columbia, 2329 W Mall, Vancouver, BC V6T 1Z4, CanadaMariely DeJesus-Hernandez - Mayo ClinicNiCole A. Finch - Mayo ClinicPatricia H. Brown - Mayo ClinicMelissa E. Murray - Mayo ClinicGing-Yuek R. Hsiung - University of British ColumbiaHeather Stewart - University of British ColumbiaAnna M. Karydas - University of California, San FranciscoElizabeth Finger - Western UniversityAndrew Kertesz - Western UniversityEileen H. Bigio - Northwestern UniversitySandra Weintraub - Northwestern UniversityMarsel Mesulam - Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA Section of Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA Division of Neurology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada Department of Neurology, University of California, 500 Parnassus Ave, San Francisco, CA 94143, USA The University of Western Ontario, 1151 Richmond St, London, ON N6A 3K7, Canada Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, 320 East Superior Street Chicago, IL 60611, USA University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA Molecular Brain Research Group, Robarts Research Institute, 100 Perth Drive London, ON N6A 5K8, Canada Banner Sun Health Research Institute, 10515 W Santa Fe Dr, Sun City, AZ 85351, USA Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA Department of Neurology, Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129, USA Department of Neurology, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ 85054, USA Department of Neurology, Mayo Clinic, 1216 2nd St SW, Rochester, MN 55902, USA Department of Pathology and Laboratory Medicine, University of British Columbia, 2329 W Mall, Vancouver, BC V6T 1Z4, CanadaKimmo J. Hatanpaa - The University of Texas at DallasCharles L. White - The University of Texas at DallasMichael J. Strong - Western UniversityThomas G. Beach - Banner Sun Health Research InstituteZbigniew K. Wszolek - Mayo ClinicCarol Lippa - Drexel UniversityRichard Caselli - Mayo Clinic, Scottsdale AZ.Leonard Petrucelli - Mayo ClinicKeith A. Josephs - Mayo Clinic Rochester, MNJoseph E. Parisi - Mayo Clinic Rochester, MNDavid S. Knopman - Mayo Clinic Rochester, MNRonald C. Petersen - Mayo Clinic Rochester, MNIan R. Mackenzie - University of British ColumbiaWilliam W. Seeley - University of California, San FranciscoLea T. Grinberg - University of California, San FranciscoBruce L. Miller - University of California, San FranciscoKevin B. Boylan - Mayo ClinicNeill R. Graff-Radford - Mayo ClinicBradley F. Boeve - Mayo Clinic Rochester, MNDennis W. Dickson - Mayo ClinicRosa Rademakers - Mayo Clinic
- Publication Details
- Acta neuropathologica, v 127(3), pp 397-406
- Publisher
- Springer Nature
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000331742800008
- Scopus ID
- 2-s2.0-84896718565
- Other Identifier
- 991019312462104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology
- Neurosciences
- Pathology